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Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators.

ABSTRACT: Complete folding is not a prerequisite for protein function, as disordered and partially folded states of proteins frequently perform essential biological functions. In order to understand their functions at the molecular level, we utilized diverse experimental measurements to calculate ensemble models of three nonhomologous, intrinsically disordered proteins: I-2, spinophilin, and DARPP-32, which bind to and regulate protein phosphatase 1 (PP1). The models demonstrate that these proteins have dissimilar propensities for secondary and tertiary structure in their unbound forms. Direct comparison of these ensemble models with recently determined PP1 complex structures suggests a significant role for transient, preformed structure in the interactions of these proteins with PP1. Finally, we generated an ensemble model of partially disordered I-2 bound to PP1 that provides insight into the relationship between flexibility and biological function in this dynamic complex.

SUBMITTER: Marsh JA

PROVIDER: S-EPMC2936704 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators.

Marsh Joseph A JA Dancheck Barbara B Ragusa Michael J MJ Allaire Marc M Forman-Kay Julie D JD Peti Wolfgang W

Structure (London, England : 1993) 20100901 9

Complete folding is not a prerequisite for protein function, as disordered and partially folded states of proteins frequently perform essential biological functions. In order to understand their functions at the molecular level, we utilized diverse experimental measurements to calculate ensemble models of three nonhomologous, intrinsically disordered proteins: I-2, spinophilin, and DARPP-32, which bind to and regulate protein phosphatase 1 (PP1). The models demonstrate that these proteins have d ...[more]

PMID: 20826336

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Project description:Disordered regions and Intrinsically Disordered Proteins (IDPs) are involved in critical cellular processes and may acquire a stable three-dimensional structure only upon binding to their partners. IDPs may follow a folding-after-binding process, known as induced folding, or a folding-before-binding process, known as conformational selection. The transcription factor p53 is involved in the regulation of cellular events that arise upon stress or DNA damage. The p53 domain structure is composed of an N-terminal transactivation domain (p53TAD), a DNA Binding Domain and a tetramerization domain. The activity of TAD is tightly regulated by interactions with cofactors, inhibitors and phosphorylation. To initiate transcription, p53TAD binds to the TAZ2 domain of CBP, a co-transcription factor, and undergoes a folding and binding process, as revealed by the recent NMR structure of the complex. The activity of p53 is regulated by phosphorylation at multiple sites on the TAD domain and recent studies have shown that modifications at three residues affect the binding towards TAZ2. However, we still do not know how these phosphorylations affect the structure of the bound state and, therefore, how they regulate the p53 function. In this work, we have used computational simulations to understand how phosphorylation affects the structure of the p53TAD:TAZ2 complex and regulates the recognition mechanism. Phosphorylation has been proposed to enhance binding by direct interaction with the folded protein or by changing the unbound conformation of IDPs, for example by pre-folding the protein favoring the recognition mechanism. Here, we show an interesting turn in the p53 case: phosphorylation mainly affects the bound structure of p53TAD, highlighting the complexity of IDP protein-protein interactions. Our results are in agreement with previous experimental studies, allowing a clear picture of how p53 is regulated by phosphorylation and giving new insights into how post-translational modifications can regulate the function of IDPs.

Dataset Information

Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators.

Publications

Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators.

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